Inflammation is a complex response to localized injury or other trauma which involves various immune-system cells and numerous mediators. Interleukin-8 (IL-8, CXCL8) and Interleukin-6 (IL-6) are some of the major mediators of the inflammatory response. They are chemokines and cytokines secreted by macrophages, endothelial cells, monocytes, fibroblasts and neutrophils and are chemotactic for neutrophils, basophils and T cells, inducing neutrophil adherence to vascular endothelium and extravasation into tissues. IL-8, IL-6 and other immune cells are activated by cis-acting transcription factors such as NFKB. The NFKB signaling cascade is hypothesized to be initiated by several independent pathways involving receptors for TNF-a, IL-1, and bacterial lipopolysaccharides (LPS), which then converge on NIK, or on members of the MAP6K family. (Eidelman et al., 2001) IL-8 and IL-6 secretion is increased by oxidant stress and can also induce oxidant stress mediators. Elevated IL-8 and IL-6 levels can therefore play a damaging role as well as aid in the healing process.
Individuals with cystic fibrosis (CF) have elevated levels of IL-8. As the cystic fibrosis patient ages, the cystic fibrosis lung becomes characterized by elevated levels of white cells including polymorphonuclear leukocytes, macrophages, monocytes, lymphocytes and eosinophils. It is hypothesized that these cells are attracted from the circulation into the airway by the high levels of IL-8 and other pro-inflammatory factors such as IL-113, IL-6, leukotriene B4, RANTES, and TNFa. These factors mark the character of the cystic fibrosis lumenal milieu (Bonfield, et al. (1995a); ibid (1995b)). Among these factors, IL-8 ranks as the most prevalent and potent. IL-8 is of specific importance for cystic fibrosis because it is profoundly elevated in bronchoalveolar lavage fluids, sputum, and serum from cystic fibrosis patients (Dean, et al. (1993); Richman-Eisenstat, et al. (1993); Francoeur. et al. (1995); Armstrong, et al. (1997)). IL-8 protein is elevated in bronchoalveolar lavage fluids from infants with cystic fibrosis as early as 4 weeks of age (Khan, et al. (1995)). Hypersecretion of IL-8 occurs prior to objective evidence of infection by viruses, fungi or common cystic fibrosis pathogenic bacteria (Khan, et al (1995)). The concept of the generality of a pro-inflammatory state for cystic fibrosis epithelia is further manifest by the fact that fecal IL-8 levels in cystic fibrosis children are approximately 1000-fold elevated over non-cystic fibrosis controls (Briars, et al. (1995)). Fecal IL-8 levels correlate with lung function (FEV1, forced expiratory volume in one second), and to some extent with established Pseudomonas infection. A study with bronchial biopsies from cystic fibrosis patients undergoing lung transplant has demonstrated consistent up-regulation of IL-8 expression in submucosal gland cells (Tabary et al. (1998)).
It would therefore be desirable to develop compositions that reduce excessive inflammation, particularly compositions that reduce the secretion of IL-8 and other pro-inflammatory cytokines from cells secreting elevated levels of these compounds. These compositions could be useful in the treatment of disease conditions characterized by elevated levels of inflammatory cytokines.